This is a renewal application to study anti-HIV polyribonucleotides. Previous results show that 1-methyl-6-mercaptopurine and 1-methyl-6-thioguanine containing polyribonucleotides exhibit potent anti-HIV activity and that the hydrophilic polymer containing 1-amino-6-mercaptopurine is devoid of activity. This information is consistent with the hypothesis that amphiphilic character and ability to form a helical array in solution may be important factors in the anti-HIV activity of these compounds. Potent activity was also demonstrated against human cytomegalovirus including both ganciclovir-sensitive and ganciclovir-resistant strains. The present proposal has six specific aims: (1) Continue design and synthesis of nucleoside 5'-diphosphates intended to afford novel amphiphilic (hydrophilic backbone, hydrophobic bases) properties with improved anti- HIV and anti-CMV activity; (2) Pursue avenues for enhancing the efficiency of polynucleotide synthesis from these diphosphates; (3) Explore the serum stability of poly(1-methyl-6-thioinosinic acid) [PMTI] and other compounds which may result from the synthetic effort; (4) Explore the antiviral activity and mechanism of action of the polymers against HIV and HCMV in collaboration with Drs. Buckheit and Sidwell; (5) Continue to associate biological activity with polynucleotide structure, both primary sequence and secondary structure; and (6) Allow the structure activity relationships that are developed to drive the synthetic program.